Process for the production of delta5-3-keto and delta4-3-keto steroids



PROCESS FOR THE PRODUCTION OF A -3-KETO AND A -3-KET0 STEROIDS Carl Djerassi, Birmingham, and Robert R. Engle,- Detroit, Mich.

No Drawing. Application May 27, 1957 Serial No. 661,616

Claims priority, application Mexico May 29, 1956 '11 Claims. (Cl. 260-3973) The present invention relates to a novel process for the production of cyclopentanophenanthrene derivatives.

More particularly the present invention relates to a process for the production of steroidal A -3-ketones and A -3-ketones by controlled chromic acid oxidation of the corresponding A -3-hydroxy compounds.

Although chromic acid has heretofore been used for the oxidation of steroidal 3-alcohols to 3-ketones it has not been thought possible to use this oxidizing agent in steroids with the reactive 5-6 double bond because of the re action of the chromic acid with the double bond. Where chromic acid has been used as an oxidizing agent for compounds of this character the double bond was first protected by bromination, the brominated compound oxidized and the bromine was then removed. These additional steps of bromination and debromination therefore always caused a lowering of the yield of the desired 3-ketone. Further, it was difiicult by prior art methods to prepare A -3-keto compounds.

In accordance with the present invention it has been discovered that under controlled conditions in the presence of acetone or methylethyl ketone steroidal A -3-alcohols may be oxidized with chromic acid to A -3-ketones in high yield and that these compounds upon isomerization gave the corresponding A 3-ketones. There has further been discovered and prepared according to the present invention certain new A 3-ketones of the androstane and pregnane series namely A -pregnen-21-ol-3,20- dione and its esters, l7a-lower alkyl-A -androsten-1718- -ol-3-one and l7ot-ethinyl-A -androsten-l7B-ol-3-one. The first of these novel compounds A -pregnen-2l-ol-3,2O- dione and its esters was a valuable cortical hormone having the properties of desoxycorticosterone and its esters but free of salt retention effects. The l7a-lower alkylandrosten-l7fl-ol-3-one compounds and 17u-ethinyl-A androsten-l'US-ol-B-one were useful hormones of the androgenic type.

The process of the present invention may be exemplified by the following equation:

atent rm ice In the above equation R represents substituents at C-l7 ordinarily found in compounds of the pregnene and androstene series except for primary or secondary alcohol.

where R is the esterification residue of a hydrocarbon carboxylic acid of less than 12 carbon atoms,

where R is a lower alkyl group such as methyl or ethyl,

r-OE, -o-on,on' o'scn etc.

In practicing the process, the A -3-hydroxy steroid preferably of the androstene or pregnene series is dissolved in acetone or methylethyl ketone. The ketone is preferably used in large amount as compared to the steroid so that a solution of from 0.5 to 1.5% by weight is formed. Gentle warming may be used for the solution and the solution is then cooled in an ice bath to less than 20 C. Thereafter there is added oxidizing reagent comprising chromium trioxide dissolved in a solution of sulphuric acid to form in situ'chromic acid. Preferably the oxidation reagent is added quickly and in an amount approximately equivalent to one equivalent of active oxygen (based on the steroid). In preparing the oxidation reagent 26 g. of chromium trioxide is mixed with 23 cc. of concentrated sulfuric acid and diluted to a total volume of cc. and. in general the sulfuric acid content should not be less than about 15 cc. or more than about 25 cc. After the oxidizing reagent is added the reaction is allowed to proceed for a short period of time of the order of 2 minutes, a time of from 1 to 10 minutes being suitable While the temperature is maintained below 20 C. The reaction mixture is then diluted with water and the precipitated 3-keto-A product purified as by crystallization.

For the second step of the process outlined above the 3-keto-A -steroid is dissolved in a polar organicsolvent and a small amount of an aqueous solution of base such as an alkali metal hydroxide or acid such as sulfuric or hydrochloric added. The mixture is then heated for a short time and then neutralized. The product is conventionally recovered as by concentration, extraction etc.

The following specific examples wherein the previously mentioned oxidizing reagen was used serve to illustrate but are not intended to limit the present invention.

Example I 3. g. of M-pregnen-3fl-ol-20-one was dissolved in 400 cc. of acetone with gentle warming and the mixture was cooled in an ice bath to a temperature of 10-15" C., which was maintained during the reaction period. To the stirred cool solution there was added 2.75 cc. of the oxidizing reagent and after 2 minutes the reaction mixture was diluted with water to a volume of 2 l. The white precipitate which separated was collected to give a residue of 2.7 g. Crystallization from ethyl acetate at the temperature of a. Dry Ice bath afforded A -pregnene-3,20- dione, M.P. 139-148", [111 +60 (chloroform), infrared band at 5.85 M.P. of isolated carbonyl groups. Note.- The above reaction was carried out since the beginning under an atmosphere of nitrogen, and all the reagents, solvents, etc.-used were treated with nitrogen before use to have an atmosphere free of oxygen.

2.7 g. of A -pregnene-3,2O-dione was dissolved in methanol by heating on the steam bath, and mixed with 3 drops of a aqueous solution of potassium hydroxide. The mixture was heated for 5 minutes and then acetic acid was added to neutralize the alkali. Again, this operation was carried out under an atmosphere of nitrogen. The solution was then concentrated to half of its volume, diluted with water and extracted with ether. The ether solution was washed, dried over anhydrous sodium sulfate and evaporated to dryness, thus producing 2.64. g. of crude progesterone, M.P. 113l31 C., [041 +182 (chloroform). Chromatographic purification afiorded 2.31 g. of pure progesterone.

Example 11 A stirred solution of 1 g. of the 2l-monoacetate of A -pregnene-3fi,2l-diol-2O-one in 80 cc. of acetone previously cooled to C. was mixed with 0.9 cc. of the oxidizing reagent and after 2 minutes the mixture was diluted with Water to a total volume of 1 l. The white precipitate of A -pregnen-2l-ol-3,20-dione acetate was collected. Crystallization from acetone afiorded the pure product, M.P. 123-137" C., [@1 +69".

Similar reaction with other 21-esters such as the propionate, benzoate as well as other esters of hydrocarbon carboxylic esters of less than 12 carbon atoms gave the corresponding 2l-esters of A -pregnen-2l-ol-3,2O-dione.

These operations were carried out under nitrogen, with materials previously treated with nitrogen to exclude atmospheric oxygen.

2.7 g. of the above compound was dissolved in methanol and isomerized with 15% aqueous potassium hydroxide, such as has been described in Example I, thus producing an oily residue of A -pregnen-21-ol-3,20-dione. This was dissolved in a mixture of 25 cc. of pyridine and 25 cc. of acetic anhydride and kept standing for 16 hours. The mixture was poured in ice and the precipitate of crude desoxycorticosterone acetate was filtered. Chromatography in a column with 100 g. of acid washed alumina,

followed by crystallization from acetone, yielded 1.9 g. e

of pure desoxycorticosterone acetate, M.P. 156157.5 C.

Example III l7a-methyl-A -androsten-3fi,l7fi-diol was treated by the method described in Example I thus producing, respectively, 17a-methyl-A -androsten-17fi-ol-3-one and 17amethyl-M-androsten-l7B-ol-3-one. Similar reaction with l7a-ethyl-A -androsten-35,l7 3-diol gave first l7m-ethyl- A -androsten-17fi-ol-3-one and 17a-ethyl-A -androsten- 17B-ol-3-one.

Example IV 17a-ethinyl-A -androsten-3 3,l7fi-dio1 was treated by the method described in Example I, thus producing, respectively, 17a-ethinyl-A -androsten-17B-ol-3-one and 17aethinyl-Aendrosten-17B-ol-3-one.

Example V The 17-acetate of A -androsten-3BJ7B-diol was treated by essentially the same method as described in Example 4 I, thus giving, respectively, the 17-acetate of A -androstenl7p-ol-3-one and of testosterone.

Example VI The l7-propionate of A -androsten-3fi,17fi-diol was treated by essentially the same method as described in Example I, and there were obtained, respectively, the 17- propionate of A -androsten-l7 8-ol-3-one and of testosterone.

We claim:

1. A process for the production of steroidal A 3- ketones selected from the group consisting of A -3-ketones of the pregnene series and A -3-ketones of the androstene series comprising oxidizing the corresponding A -3-alcohols with chromic acid in the presence of a ketone selected from the group consisting of acetone and methylethyl ketone.

2. The process of claim 1 wherein the starting compounds and the products are members of the pregnene series.

3. The process of claim 1 wherein the starting compounds and the products are members of the androstene series.

4. A process for the production of steroidal A -3- ketones selected from the group consisting of A -3-ketones of the pregnene series and A -3-ketones of the androstene series comprising oxidizing the corresponding A -3-alcohols with chromic acid in the presence of a ketone selected from the group consisting of acetone and methylethyl ketone to form the corresponding A -3ketones and isomerizing the A -3-ketones with a base.

5. The process of claim 4 wherein the starting com pounds and the products are members of the pregnene series.

6. The process of claim 4 wherein the starting compounds and the products are members of the androstene series.

7. The method of claim 1 wherein the starting material is A -pregnen-3 3-ol-20-one and the product is A -pregnen- 3,20-dione.

8. The method of claim 1 wherein the starting material is 21-esters of A -pregnen-3 3,2l-diol-20-one and the product is 21-ester of A -pregnen-21-ol-3,20-dione.

9. The method of claim 1 wherein the starting material is methyl-androstendiol and the product is 17a-methyl- A -androsten-17,6-ol-3-one.

10. The method of claim 1 wherein the starting material is ethinyl-androstenediol and the product is 17methinyl-A -androsten-l7fi-ol-3-one.

11. The method of claim 1 wherein the starting material is 17-esters of A -androsten-3fi,17fi-diol and the product is 17-esters of A -androsten-17B-ol-3'one.

References Cited in the file of this patent UNITED STATES PATENTS 2,248,954 Butenandt Jluly 15, 1941 2,265,417 Bockmuhl et al Dec. 9, 1941 2,318,105 Ruzicka. May 4, 1943 2,334,695 Butenandt et al Nov. 23, 1943 2,678,933 Meister May 18, 1954 

1. A PROCESS FOR THE PRODUCTION OF STEROIDAL $5-3KETONES SELECTED FROM THE GROUP CONSISTING OF $5-3-KETONES OF THE PREGNENE SERIES AND $5-3-KETONES OF THE ANDROSTENE SERIES COMPRISING OXIDIZING THE CORRESPONDING $5-3-AL COHOLS WITH CHROMIC ACID IN THE PRESENCE OF A KETONE SELECTED FROM THE GROUP CONSISTING OF ACETONE AND METHYLETHYL KETONE. 